{"doi":"10.1172/jci.insight.156330","title":"Immune cells and their inflammatory mediators modify β cells and cause checkpoint inhibitor–induced diabetes","abstract":"Checkpoint inhibitors (CPIs) targeting programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have revolutionized cancer treatment but can trigger autoimmune complications, including CPI-induced diabetes mellitus (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induced diabetes rapidly. RNA sequencing revealed that cytolytic IFN-γ+CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFN-γ and TNF-α and included induction of a potentially novel β cell population with transcriptional changes suggesting dedifferentiation. IFN-γ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFN-γ and anti-TNF-α prevented CPI-DM in anti-PD-L1-treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway resulted in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.","journal":"JCI Insight","year":2022,"id":239092,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":51,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":571205,"name":"Songyan Deng","orcid":"0000-0001-5289-6505","position":1,"is_corresponding":false},{"id":864337,"name":"Katherine Du","orcid":"0000-0002-1715-5426","position":2,"is_corresponding":false},{"id":564370,"name":"Manik Kuchroo","orcid":"0000-0001-7512-9739","position":3,"is_corresponding":false},{"id":48974,"name":"Daniel B. Burkhardt","orcid":"0000-0001-7744-1363","position":4,"is_corresponding":false},{"id":566958,"name":"Alexander Tong","orcid":"0000-0002-2031-4096","position":5,"is_corresponding":false},{"id":865200,"name":"Gary M. Israel","orcid":null,"position":6,"is_corresponding":false},{"id":864338,"name":"Marie Robert","orcid":"0000-0002-1374-6210","position":7,"is_corresponding":false},{"id":2961,"name":"Stuart P. Weisberg","orcid":"0000-0002-8698-5976","position":8,"is_corresponding":false},{"id":476262,"name":"Nancy C. Kirkiles-Smith","orcid":null,"position":9,"is_corresponding":false},{"id":865201,"name":"Angeliki M. Stamatouli","orcid":null,"position":10,"is_corresponding":false},{"id":226323,"name":"Harriet M. Kluger","orcid":"0000-0002-4932-9873","position":11,"is_corresponding":false},{"id":308642,"name":"Zoe Quandt","orcid":"0000-0002-4568-4368","position":12,"is_corresponding":false},{"id":235280,"name":"Arabella Young","orcid":"0000-0002-6845-9753","position":13,"is_corresponding":false},{"id":815432,"name":"Mei-Ling Yang","orcid":"0000-0003-1687-2463","position":14,"is_corresponding":false},{"id":649480,"name":"Mark J. Mamula","orcid":"0000-0003-4822-2908","position":15,"is_corresponding":false},{"id":243205,"name":"Jordan S. Pober","orcid":"0000-0001-5990-1071","position":16,"is_corresponding":false},{"id":235418,"name":"Mark S. Anderson","orcid":"0000-0002-3093-4758","position":17,"is_corresponding":false},{"id":254926,"name":"Smita Krishnaswamy","orcid":"0000-0001-5823-1985","position":18,"is_corresponding":false},{"id":230352,"name":"Kevan C. Herold","orcid":"0000-0003-1534-6613","position":19,"is_corresponding":false},{"id":571209,"name":"Ana Luisa Perdigoto","orcid":"0000-0002-0348-9329","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:22:36.865157Z","pmid":"35925682","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}